This application addresses Broad Challenge Area (15) Translation Science and Specific Challenge Topic: 15-NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. Alzheimer's disease (AD) is an irreversible neurological disorder that progressively attenuates the cognitive abilities of those afflicted, ultimately leading to death. AD is the most common of all neurodegenerative disorders, with an estimated 25 million victims worldwide. As life expectancies continue to rise, AD is becoming increasingly common, and it is estimated that the number of those afflicted with AD will increase to 114 million by the year 2050, and cost over $700 billion a year if nothing is done to curb the disease. Despite intensive studies, the pathogenesis of this illness remains to be elucidated and effective therapies still await discovery. Recent findings suggest that treatment of amyloid accumulation may be insufficient for treating Alzheimer's disease, and raise the possibility that scientific and corporate research efforts have been too narrowly focused on the amyloid aspect of Alzheimer's disease. Alternative therapeutic strategies may ultimately prove to be key. In particular, targeting fundamental mechanisms of cell survival and maintenance that are disrupted in Alzheimer's disease may lead to cures of other neurodegenerative disease as well, as these downstream events are often reported in multiple age-dependent neurodegenerative disorders. Importantly, we have recently shown that deregulation of HDAC1 may be critically involved in CNS pathology that may be relevant to stroke/ischemia and Alzheimer's disease. Using an inducible p25/Cdk5 neurodegeneration mouse model, we have observed that the catalytic activity of the histone deacetylase (HDAC1), a key regulator of epigenetic modifications, was inhibited by p25/Cdk5. Loss-of-function of HDAC1 in neurons through multiple means resulted in the accumulation of DNA damage, cell cycle activity, and neuronal death. Conversely, overexpression of HDAC1 resulted in a rescue against p25-induced DNA damage and neuronal death. These results suggest a role for HDAC1 in the maintenance of DNA integrity and cell cycle suppression in adult neurons. Furthermore, overexpression of HDAC1 resulted in significant rescue against DNA damage and neurodegeneration in a rodent stroke model, demonstrating therapeutic potential for HDAC1 gain-of-function. As p25 accumulation, cell cycle reentry, and DNA damage appear to be features shared in multiple neurodegenerative conditions, it is anticipated that HDAC1 gain-of-function may be a valid therapeutic strategy against Alzheimer's disease, stroke, and other disorders. We propose here to develop a "proof-of-concept" of this strategy by identifying small molecules through a high-throughput screen that can increase the deacetylase activity of HDAC1. Preliminary results suggest the feasibility of these efforts and the ability of such small-molecule probes to prevent neurotoxicity. Given that the proposed strategy is significantly different from any of the previous therapeutic strategies that are undergoing development or have been abandoned, there is tremendous opportunity for these studies to have a high impact on human health. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to discover and characterize selective chemical activators of the HDAC1 that can be tested for the ability to prevent neurotoxicity. Findings from this application may offer novel therapeutic strategy against Alzheimer's disease, stroke, and other neurological disorders.